The goals and aims of the grant are based on previous studies showing that Qa-1 dependent CD8+ T cells play a major role in regulating peripheral self-reactive TCR repertoire by selectively down-regulating potentially pathogenic self-reactive T cells in EAE. The molecular interaction between the regulatory CD8+ T cells and target CD4+ T cells is through the recognition of Qa-1/self-peptide complex expressed on certain CD4+ T cells by the ab TCR on regulatory CD8+ T cells. Our observations lead us to propose an "affinity model" of peripheral T cell regulation by the regulatory CD8+ T cells. Basically, the affinity model proposes that whether or not a CD4+ T cell expresses Qa-1/self-peptide on their surface to induce and be specifically regulated by CD8+ T cells is dependent on the affinity of their TCR interaction with antigen/MHC class II complex on APCs during the initial antigen triggering. In this regard, it is known that following T cell activation the diversity of peptides bound to Qa-1 increases so that the activated T cells express Qa-1 molecules not only bound to the canonical Qa-1 binding peptide, Qdm, but also to self peptides induced by T cell activation. We hypothesize that these new Qa-1/self-peptide complexes are recognized by the CD8+ T cells which then differentiate to down-regulate activated CD4+ T cells expressing the same Qa-1/selfpeptide/ s. In this grant we will identify and test Qa-1 binding peptide/s which render the activated T cells susceptible to the down-regulation by the CD8+ T cells in EAE model. We will also identify the peripheral self-reactive repertoire and the relationship between affinity/avidity and pathogenicity of self-reactive T cells in EAE model to further understand how preferential down regulation of certain affinity/avidity clones by the Qa-1 dependent CD8+ T cells provides a mechanism to control the pathogenic auto-immunity in the periphery. In addition, we will characterize the immune functions of the Qa-1 dependent CD8+ T cells in EAE by identifying the TCR Va and Vb repertoire of the CD8+ T cells and defining the other immunologic functions mediated by CD8+ T cells. The overall goal of this grant is to understand not only the theoretical basis of the immuno-regulatory pathway mediated by the Qa-1 dependent CD8+ T cells in control of auto-immunity but also the potential application of this pathway in treating auto-immune disease. In this regard, our studies will provide new insight into the general biology of peripheral T cell regulation and basic mechanisms by which the immune system could be manipulated to specifically suppress potentially pathogenic auto-immune responses.